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Nitrite circumvents canonical cGMP signaling to enhance proliferation of myocyte precursor cells

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Abstract

Skeletal muscle tissue has a remarkable high regenerative capacity. The underlying cellular events are governed by complex signaling processes, and the proliferation of skeletal myoblasts is a key initial event. The role of nitric oxide (NO) in cell cycle regulation is well-appreciated. Nitrite, an NO oxidation product, is a stable source for NO-like bioactivity particularly in cases when oxygen shortage compromises NO-synthases activity. Although numerous studies suggest that nitrite effects are largely related to NO-dependent signaling, emerging evidence also implicates that nitrite itself can activate protein pathways albeit under physiological, normoxic conditions. This includes a recently demonstrated cyclic guanosine monophosphate-(cGMP)-independent enhancement of endothelial cell proliferation. Whether nitrite itself has the potential to affect myoblast proliferation and metabolism with or without activation of the canonical NO/cGMP pathway to subsequently support muscle cell regeneration is not known. Here we show that nitrite increases proliferation and metabolic activity of murine cultured myoblasts dose-dependently. This effect is not abolished by the NO scavenger 2-(4-carboxy-phenyl)-4,4,5,5-tetramethylimida-zoline-1-oxyl-3 oxide and does not affect intracellular cGMP levels, implicating a cGMP-independent mechanism. Nitrite circumvents the rapamycin induced attenuation of myoblast proliferation and enhances mTOR activity. Our results provide evidence for a novel potential physiological and therapeutic approach of nitrite in skeletal muscle regeneration processes under normoxia independent of NO and cGMP.

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Acknowledgments

MT was supported by a scholarship from the German Heart Foundation (Deutsche Herzstiftung) and by a Grant from the Forschungskommission of the Medical Faculty of the University of Duesseldorf. AS is a scholar of the Studienstiftung des Deutschen Volkes. TR is a Heisenberg professor funded by the DFG (RA969/7-2). TR was supported by a grant from the DFG (RA969/4-2).

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The authors declare that they have no conflict of interest.

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  1. Division of Cardiology, Pulmonology and Vascular Medicine, Department of Medicine, Medical Faculty, University Hospital Duesseldorf, Moorenstrasse 5, 40225, Düsseldorf, Germany

    Matthias Totzeck, Andreas Schicho, Pia Stock, Malte Kelm, Tienush Rassaf & Ulrike B. Hendgen-Cotta

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  1. Matthias Totzeck
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  2. Andreas Schicho
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  3. Pia Stock
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  6. Ulrike B. Hendgen-Cotta
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Correspondence to Ulrike B. Hendgen-Cotta.

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Totzeck, M., Schicho, A., Stock, P. et al. Nitrite circumvents canonical cGMP signaling to enhance proliferation of myocyte precursor cells. Mol Cell Biochem 401, 175–183 (2015). https://doi.org/10.1007/s11010-014-2305-y

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  • DOI: https://doi.org/10.1007/s11010-014-2305-y

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